Drug Dosing Consideration in Patients With Acute and Chronic Kidney Disease

A Clinical Update From Kidney Disease: Improving Global Outcomes (KDIGO)

Gary R Matzke; George R Aronoff; Arthur J Atkinson Jr; William M Bennett; Brian S Decker; Kai-Uwe Eckardt; Thomas Golper; Darren W Grabe; Bertram Kasiske; Frieder Keller; Jan T Kielstein; Ravindra Mehta; Bruce A Mueller; Deborah A Pasko; Franz Schaefer; Domenic A Sica; Lesley A Inker; Jason G Umans; Patrick Murray


Kidney Int. 2011;80(11):1122-1137. 

In This Article

Assessment of Kidney Function

The standard measure of kidney function for decades has been the glomerular filtration rate (GFR).[7] The measurement of GFR can be accomplished using many exogenous substances. Urinary clearance of inulin, which is the gold standard, is rarely performed except for research purposes because of the limited availability of the substance and the labor intensity of the procedure and the assay.[8] Modifications to this procedure include the use of other exogenous agents such as iothalamate, iohexol, and (99 m)Tc/c-diethylenetriamine pentaacetic acid, and plasma clearance to replace the need for urine collections. These are all more commonly available and utilized, but have limitations.[9] For example, some of the markers are not completely eliminated by GFR but are secreted by the tubules. Calculation of plasma clearance requires extrapolation of the area under the curve (AUC), which is often unreliable in those with the greatest degree of kidney function impairment or those with extensive edema, and even with these markers, the procedures are cumbersome and subject to error unless done under careful controlled conditions.[10] The determination of GFR based on the administration of exogenous substances is not practical for routine individual drug dose calculations as they are not timely and not uniformly available.

The determination of GFR utilizing an endogenous substance has therefore been based on the urinary clearance of creatinine (CLcr) derived from a 24 h urine collection.[7,11,12] This method is of limited clinical value because of frequent urine collection errors (even when relatively short urine collection durations of 2–12 h are utilized), analytical interference with the serum or urine creatinine assay as the result of concomitant diseases and drug therapies, and the associated delay in the reporting of the results.[8] Therefore, GFR is predominantly estimated in clinical practice from the measurement of endogenous substances such as serum creatinine (Scr) and then combined with patient factors to estimate the GFR using estimating equations.[13–19] The advantage of this method is that the results are available for routine clinical practice, and that for the majority of people, estimated GFR provides an unbiased assessment of measured GFR.[17] Estimating equations are on average more accurate than measured creatinine clearance, given the errors in urine collection (Table 1).[17]

There are limitations to Scr. In particular, because Scr is generated from muscle mass and diet, individuals at the extremes of these factors (for example, amputee or conversely body builders, or those on a vegan diet) will have substantially different values of creatinine than expected, and therefore the estimated GFR will be higher or lower than the true GFR for an individual patient and imprecision of the equation overall.[20] This limitation of Scr is regardless of which equation is used to estimate GFR, and cannot be overcome by an adjustment of the equation.[9]

Another limitation of Scr is the variability in Scr assays. The variation in the assays led to differences in reported Scr values among laboratories as well as within laboratories over time, even when the same methods are used.[21] This variation leads to differences in estimated GFR values when these different assays are used. In 2005, the National Institute of Standards and Technologies released materials that are traceable to the certified reference materials for creatinine whose value was assigned using isotope dilution mass spectroscopy (IDMS).[22,23] It is now estimated that the majority of laboratories currently report creatinine values traceable to this reference method. It is not possible to determine the precise relationship between IDMS-standardized Scr values and prior values because of the substantial variability even within the same method in their creatinine results. For example, creatinine measurements by the various Jaffe methods yield Scr values that are 5–10% higher on average than determinations by the IDMS technique. Although some have proposed a singular 'correction' value approach when using equations that were derived from creatinine measured by the Jaffe method (SCr (IDMS)=0.92 × SCr (Jaffe)), this is not a valid approach given the wide variability among and within methods described above. Recently, some have proposed and developed a methodology to convert IDMS-traceable Scr values into non-IDMS-calibrated Scr values for application in CLcr calculations to determine drug dosage adjustments.[24] This institution-specific methodology avoids the inappropriate 'generalization' of one correction factor to many patient care settings but it may not be feasible for most clinicians to utilize in their practice. The use of IDMS creatinine assays will likely lead to less variation in kidney function estimates and theoretically more consistent drug dosing recommendations across institutions and clinical settings. However, the variation in the creatinine assays before the availability of standardized creatinine assays does effect the relationships from PK/PD drug studies of the past, and therefore interpretation of product label drug dosing recommendations in the current era.[25] Estimated GFR based on current creatinine assays are likely to yield different drug dosage recommendations from those intended by the original study even if the same estimating equation is used because of this change in analytical methodology. It is not possible or practical to repeat all of the PK studies with standardized creatinine, and therefore as discussed in the section below 'drug dosing consideration for patients with CKD', it is still reasonable to use drug dosing adjustments in the product labeling.

Historically, the most frequently clinically used equation to estimate GFR has been the Cockcroft and Gault (CG) equation[13] (see Table 1). This equation provides an estimate of measured CLcr and has been widely used as an estimate of GFR as well, despite the fact that creatinine also undergoes tubular secretion. The CG equation is reported in units not adjusted for body surface area, which is appropriate for drug dosage adjustment. The CG equation has been shown to overestimate GFR with the use of standardized creatinine assays.[26] Many have considered that an advantage of the CG equation for individual drug dose adjustment is that the body weight is considered; however, this has not been validated. Similarly, many modifications to the CG equation have been proposed, such as use of lean body mass when estimating GFR in obese patients, but this too has not been validated.[27]

The Modification of Diet in Renal Disease (MDRD) Study equation was developed from an extensive sample of patients with CKD, all of whom had a measured GFR using urinary clearance of 125I iothalamate of <90 ml/min per 1.73 m2 (ref.[28]). This equation is now widely reported by clinical laboratories around the world whenever Scr is reported.[29] The MDRD Study equation has been shown to overestimate measured GFR in those with values >60 ml/min per 1.73 m2, and hence specific values are only reported for values <60 ml/min per 1.73 m2 (ref.[29]). The CKD-Epidemiology Collaboration (CKD-EPI) equation was recently developed specifically to overcome this limitation. It is more accurate than the MDRD Study equation, particularly at higher levels of GFR.[17,30] The CKD-EPI equation is now reported by Quest and LabCorp, the two largest laboratory service providers in the United States, and with it the GFR estimates are now reported throughout the GFR range.

Hence, which one of the many GFR estimation equations should be used for assessment of an individual patient's GFR as the guide to the degree of adjustment of their drug dosage regimens? The pros and cons of the various GFR-estimating equations have been extensively reviewed and there is no compelling evidence of the superiority of any given method for drug dosing in all patient populations or clinical situations.[27,31–35] Most of these studies have all compared the equations with each other in hypothetical simulations and not with actual drug clearance.[36–44] The National Kidney Disease Education Program (NDKEP) in the United States recommends that the GFR estimated from the MDRD Study or CLcr estimates from the CG equation for adults or the Schwartz equation for children can be used for drug dosing.[22] For very large or very small people, they recommend adjustment of the estimated GFR (eGFR) from the MDRD Study equation to account for patient's body surface area (BSA) ((eGFRIND=eGFRMDRD × (BSA per 1.73 m2)) to yield a eGFRIND in units of ml/min.[25,34]

It is most important that clinicians have ready access to at least one GFR estimate for all of their patients. Currently, the CKD-EPI method is the most accurate method for estimation of GFR,[17] and it appears to be emerging as the method of choice for the staging of CKD. Although documentation of its utility for drug dosing is limited,[45] it is likely to be similar to the MDRD Study equation given the similar performance at lower levels of GFR, where dose adjustment is frequent. Clinicians should use the method that provides the most accurate assessment of GFR. In particular, this is of utmost importance for those drugs with a narrow therapeutic index for which dosing individualization is required. In those clinical situations where any creatinine-based estimation equation is not likely to provide a good estimate of GFR, measured creatinine clearance or measured GFR using exogenous markers should be considered (Table 2).[22]


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